Heart failure (HF) is primarily a condition of the elderly, and thus the widely recognized “aging of the population” contributes to the increasing incidence of HF. The incidence of HF approaches 10 per 1000 population after age 65 and approximately 80% of patients hospitalized with HF are more than 65 years old.
Heart failure is a major and growing public health problem in the developed countries. In the United States approximately 7 million patients have HF, and more than 550 000 patients are diagnosed with HF for the first time each year. The disorder is the primary reason for 12 to 15 million office visits and 6.5 million hospital days each year.
Heart failure is the most common Medicare diagnosis-related group (i.e., hospital discharge diagnosis), and more Medicare dollars are spent for the diagnosis and treatment of HF than for any other diagnosis.
In Europe, the epidemiology is not well known; it is estimated that about 30 millions patients suffer from heart failure.
Cell transplantation and tissue engineering to the diseased heart are emerging as promising strategies to prevent or to treat refractory heart failure that cannot successfully be treated by conventional therapies. The advances in cellular biology, in biological engineering and nanotechnologies give further advances in this option. Implanting exogenous cells supported by scaffolds in the myocardial scar tissue to replace the damaged or the disabled cells is a safe and efficient therapeutic approach.
Stem Cell Niche and Cell Homing
After myocardial infarction, not only the changes affect the contractile element of the myocardium (cardiomyocytes) but also the extracellular matrix. The collagen type I percentage decreases from 80% to 40%, this collagen is responsible with the other elements of the heart muscle of the normal ventricular geometry.
The efficiency of cell therapy to augment recovery after myocardial ischemia depends on the sufficient recruitment of applied cells to the target tissue. Homing to sites of active neovascularization is a complex process depending on a timely and spatially orchestrated interplay between chemokines (e.g. SDF-1), chemokine receptors, intracellular signalling, adhesion molecules (selectins and integrins) and proteases.
Until now, cell transplantation for cardiac support and regeneration was limited by poor effects in ventricular function. This can be due to the lack of gap junctions between the native myocardium and the grafted cells. Also, cell transplantation seems to be limited by the relocation of transplanted cells to remote organs and noninfarcted myocardium and by the death of transplanted cells. Most cell death occurs in the first few days post-transplantation, likely from a combination of ischemia, apoptosis and inflammation. Apoptosis can be induced by anchorage-dependent cells detaching from the surrounding extracellular matrix.
The cell niche, a specialized environment surrounding stem cells, provides crucial support needed for cell maintenance. Compromised niche function may lead to the selection of stem cells that no longer depend on self-renewal factors produced by its environment. Strategies for improving cell survival and differentiation such as tissue engineering, has been developed.
Cardiac Tissue Engineering
Extra cellular matrix remodeling in heart failure (excessive matrix degradation and myocardial fibrosis) contributes to Left Ventricular (LV) dilatation and progressive cardiac dysfunction. Myocardial tissue engineering should provide structural support to the heart, specific scaffolds should help to normalize cardiac wall stress in injured regions improving strain distribution. Engineering materials requiring specific properties of stiffness and resistance to deformation can be implanted or seeded into the myocardial tissue. They are composed of natural or synthetic structure capable of supporting 3D tissue formation. Survival and engraftment of cells within the environment of the ischemic myocardium represents a challenge for all types of cells, regardless of their state of differentiation. Scaffolds characteristics are critical to recapitulating the in vivo milieu and allowing cells to influence their own microenvironments. Such scaffolds serve at least one of the following purposes: allow cell attachment and migration, deliver and retain cells and biochemical factors, enable diffusion of vital cell nutrients and expressed products, and exert certain mechanical and biological influences to modify the behavior of the cell phase. In addition, development of gap junctions within the new created tissue as well as with the host myocardial tissue are of great functional interest.
Ventricular Chamber Restoration
Restoration of ventricular shape and geometry is a surgical procedure designed to restore or remodel the left and/or right ventricle to its normal, conical shape and size in patients with akinetic segments of the heart, secondary to either post infarction cardiomyopathy or dilated cardiomyopathy. The restoration procedure can be performed during or after coronary artery bypass grafting (CABG), mitral valve repair or replacement and other procedures such as implantation of stem cells for myocardial regeneration. Surgical ventricular restoration has been performed: 1) by partial resection of the ventricular wall using cardiac arrest and cardiopulmonary bypass (extracorporeal circulation), or 2) by external ventricular remodelling, e.g. cardiac wrapping with autologous tissues like the latissimus dorsi muscle flap. Ventricular restoration procedure with bioactive implants avoids cardiac arrest and extracorporeal circulation.
Ventricular Restraint Therapies
Heart failure patients develop oversized, dilated hearts due to increased filling pressures. Over time the increased workload of the heart can lead to a change called remodeling, which is the enlargement and thinning of the ventricles. The failing cardiac muscle need to be supported to decrease the ventricular wall stress. Mesh wrap devices that are implanted around the heart have been used. These devices are intended to prevent and reverse the progression of heart failure by improving the heart's structure and function, leading to improvements in the survival and quality of patient's life. For example, implantable devices have been tested for ventricular restraint therapy, like polyester netlike sack designed for placement around the heart fabricated into a multifilament mesh knit (CorCap device, Acorn). Also a nitinol mesh for ventricular wrapping was investigated (HeartNet device, Paracor). Permanent implantation experience of both devices showed adverse effects like restriction in diastolic function and lack of improvement of systolic function, without evidence of myocardial healing. These results have limited its large clinical application, including the “not to approve” U.S. Food and Drug Administration (FDA) decision.
Translational Research
Experimental and clinical studies have been performed on stem cell therapy and tissue engineered approaches for myocardial support and regeneration. The results of these investigations tend to demonstrate the interest of simultaneous intrainfarct stem cell therapy with the fixation of cell-seeded matrices onto the epicardium of infarcted ventricles.
Experimental studies suggest that simultaneous autologous intramyocardial injection of stem cells and fixation of a cell-seeded collagen matrix onto the epicardium is feasible. However, the long-term efficacy of this approach is compromised by the complete biodegradation of the grafted collagen matrix.
WO2006/036826 discloses a tissue-engineering scaffold containing self-assembled-peptide hydrogels.
US2005/0095268 describes a cardiac wall tension relief with cell loss management.
The article of Boublik et al. (Tissue engineering, 2005) relates to the mechanical properties and remodelling of hybrid cardiac constructs made from heart cells, fibrin, and biodegradable, elastomeric knitted fabric.
In summary, the following problems are encountered in the field of myocardial repair.
1) It is difficult to repair a large myocardial scar.
2) Cell bio-retention and engraftment within scar tissue is too low.
3) Mortality of implanted cells in ischemic myocardium is high.
4) Extracellular matrix remodeling in ischemic heart disease (excessive matrix degradation and myocardial fibrosis) contributes to LV dilatation and progressive cardiac dysfunction.
5) The therapeutic limitation of heart dilatation and the recovery of the native elliptical shape of ventricular chambers are key prognostic factors for survival in HF patients.
6) In cell transplantation, survival and engraftment within the environment of the ischemic myocardium represents a challenge for all types of cells, regardless of their state of differentiation.
7) Up to now, the optimal cell-matrix combination for robust and sustained myocardial restoration has not been identified.
8) The long-term efficacy of the approach—autologous intramyocardial injection of stem cells and fixation of a cell-seeded collagen matrix onto the epicardium—is compromised by the complete biodegradation of the grafted collagen matrix.
9) There are undesired effects of growth factor administration.
10) Tissue viability/evolution over time.